Transcript Document

Cardiometabolic
Risk
Faculty of Medicine
Universitas Brawijaya
Malang

A comprehensive approach to patient care;
Multiple disease pathways and risk factors
are considered to facilitate earlier intervention

Early assessment and targeted intervention
are needed to treat and prevent all risk
factors associated with CVD and diabetes

Gives a comprehensive picture of a patient’s health
and potential risk for future disease and
complications

Is inclusive of all risks related to metabolic changes
associated with CVD
 Accommodates emerging risk factors as useful
predictive tools

Focuses clinical attention to the value of systematic
evaluation, education, disease prevention and
treatment

Supports an integrated approach to care
Kahn, et al. The Metabolic Syndrome: Time for a Critical Appraisal: Joint Statement From the American
Diabetes Association and the European Association for the Study of Diabetes Diabetes Care. 2005;28 (9)2289-2304.
 2 out of 3 Americans are overweight or obese
 More than 70 million (nearly 1 in 4) Americans have
varying degrees of insulin resistance
 There are an estimated 54 million (more than 1 in 6)
Americans with prediabetes
 Nearly 1 in 4 U.S. adults has high cholesterol
 1 in 3 American adults has high blood pressure
Direct and Indirect Cost of CVD and Diabetes
Estimated Direct
Medical Costs
Estimated Indirect Costs
Cardiovascular
Disease
$296 billion
$152 billion
Diabetes
$116 billion
$58 billion
TOTAL
$412 billion
$210 billion
(disability, work loss,
premature mortality)
*Note: these figures may not account for potential overlap.
Sources: 2008 statistics from the American Diabetes Association and American Heart Association.
Overweight / Obesity
Age
Abnormal Lipid
Metabolism
Genetics
Insulin Resistance
LDL 
ApoB 
HDL 
Trigly. 
Insulin Resistance ?
Syndrome
 Lipids BP Glucose
Cardiometabolic
Risk
Global Diabetes / CVD Risk
Smoking
Physical Inactivity
Unhealthy Eating
Age, Race,
Gender,
Family History
Inflammation
Hypercoagulation
Hypertension
Non-modifiable
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


Age
Race/ethnicity
Gender
Family history
Modifiable

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
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Overweight
Abnormal lipid metabolism
Inflammation, hypercoagulation
Hypertension
Smoking
Physical inactivity
Unhealthy diet
Insulin resistance
 47-year-old African American man, hasn’t
seen doctor in years
 Works as a truck driver, eats mostly fast
food
 Smokes 1 pack per day
 At health fair found to have BP = 146/86,
total cholesterol = 210
 Weight = 230 lbs; BMI = 29 kg/m²
 Family history of HTN and diabetes
 Age
 Race/ethnicity
 Gender
 Family history
47
African American
Male
HTN and diabetes

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
BMI = 29
TC = 210
BP = 146/86
1 pack per day
Yes
Fast food diet
Overweight/obesity
Abnormal lipid metab
Hypertension
Smoking
Physical Inactivity
Unhealthy diet
Number
800,000
600,000
400,000
200,000
0
20-39
40-59
Age Group
60+
Centers for Disease Control and Prevention. National diabetes fact sheet: general information and national
estimates on diabetes in the United States, 2005. Atlanta, GA: U.S. Department of Health and Human Services,
Centers for Disease Control and Prevention, 2005.
39.2
45
40
35
30.8
33.6
33.1
28.2
1960-1962
29.3
27.2
30
25
36.0
19.0
17.0
20
26.3
1971-1975
26.4
1976-1980
1988-1994
1999-2000
14.8
14.9
5.0
4.6
15
3.5
3.4
1.8
10
5
0
High Total
Cholesterol
High Blood
Pressure
Smoking
Centers for Disease Control & Prevention, Division for Heart Disease and
Stroke Prevention, "Addressing the Nation's Leading Killers: At A Glance 2007
Diagnosed
Diabetes
American Indians/
Alaska Natives
Non-Hispanic Blacks
Hispanic/Latino Americans
Non-Hispanic Whites
0
2
4
6
8
10
12
14
16 18 20
Centers for Disease Control and Prevention. National diabetes fact sheet: general information and national
estimates on diabetes in the United States, 2005. Atlanta, GA: U.S. Department of Health and Human Services,
Centers for Disease Control and Prevention, 2005.
•
•
•
•
•
•
•
Overweight/ fat distribution
Age
Genetic predisposition
Activity level
Medications
Puberty
Pregnancy
• Impaired Fasting Glucose (IFG): a condition in
which the blood glucose level is between 100
mg/dL to 125mg/dL after an 8- to 12-hour fast.
• Impaired Glucose Tolerance (IGT): a condition in
which the blood glucose level is between 140
and 199 mg/dL at 2 hours during an oral glucose
tolerance test (OGTT).
Healthy BG
FPG < 100 mg/dL
Pre-diabetes
FPG 100–125 mg/dL
Diabetes
FPG ≥126 mg/dL
 Overweight (BMI > 85th percentile for age and sex, weight
for height > 85th percentile, or weight
 >120 percent of ideal for height) Plus any two of the
following:
• Family history
• Race/ethnicity
• Signs of insulin resistance or conditions associated with
insulin resistance
• Maternal history of diabetes or GDM
1. Testing should be considered in all overweight adults
(BMI ≥25 kg/m2*) and have additional risk factors:
 Physical inactivity
 First-degree relative with diabetes
 Members of a high-risk ethnic population
 Women delivering baby weighing >9 lb or
were diagnosed with GDM
 Hypertension (≥140/90 mmHg)
Continued
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

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
HDL cholesterol level <35 mg/dl (0.90 mmol/l) and/or
a triglyceride level >250 mg/dl (2.82 mmol/l)
Women with polycystic ovarian syndrome (PCOS)
IGT or IFG on previous testing
Other clinical conditions associated with insulin
resistance (e.g., severe obesity and acanthosis
nigricans)
History of CVD
2. In the absence of the above criteria, testing for prediabetes and diabetes should begin at age 45 years
3. If results are normal, testing should be repeated at least
at 3-year intervals, with consideration of more frequent
testing depending on initial results and risk status.
*At-risk BMI may be lower in some ethnic groups.
(n=943)
CHD mortality, per 1000
3
P<.01
2
1
0
29
30-50
51-72
73-114
115
Quintiles (pmol) of fasting plasma insulin
Insulin Sensitive
Fontbonne AM, et al. Diabetes Care. 1991;14:461-469.
Insulin Resistant
Cardiometabolic Risk
Insulin Sensitivity
Insulin Secretion
Associated Risk Factors
• Hypertension
• Dyslipidemia
Atherogenesis
Microvascular
Complications
Fasting Blood Glucose
Euglycemia
Age (years)
Type 2 Diabetes
Cardiometabolic Risk
Factors
Overweight/obesity
Source: CDC , ADA
Abnormal lipid metabolism
High LDL cholesterol
Low HDL cholesterol
High triglycerides
Desired Goals for Healthy Patients
Prevention of overweight/obesity as measured by BMI
(normal = 18.5–24.9).
In those who are overweight/obese, the goal is to lose 5–7%
of body weight.
Desirable levels are less than 100 mg/dL.
Desirable levels are greater than 40 mg/dL in men and
greater than 50 mg/dL in women.
Desirable levels are less than 150 mg/dL
Source: NHLBI, ATP III Guidelines, ADA
Source: NHLBI, JNC7
<140/90 mm/Hg or 130/80 mm/Hg for people with diabetes
(Ideal is less than 120/80 mm/Hg)
Fasting blood glucose
Below 100 mg/dL
Hypertension
Source: ADA
Physical inactivity
Source: CDC
At least 30 minutes of moderate activity most days
Smoking Source: ADA
Quit or never start
Children
Maintain healthy weight for age, sex, and height.
Source: ADA


Measure BMI routinely at each regular check-up.
Classifications:
• BMI 18.5-24.9 = normal
• BMI 25-29.9 = overweight
• BMI 30-39.9 = obesity
• BMI ≥40 = extreme obesity
Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults: The Evidence Report. NIH
Publication # 98-4083, September 1998, National Institutes of Health.

Large waist circumference (WC) can identify
some at increased risk over BMI alone

If BMI and other cardiometabolic risk factors
are assessed, currently there is insufficient
evidence to:
– Substitute WC for BMI
– Measure WC in addition to BMI
Klein, et al. Waist Circumference and Cardiometabolic Risk. Diabetes Care. 2007 0: dc07-9921v1-0.
Primary
Metabolic
Disturbance
Intermediate
Vascular Disease
Risk Factor
Intravascular
Pathology
Clinical
Event
Insulin
Resistance
Hypertension
Dyslipidemia
Hyperglycemia
Overnutrition
Hyperinsulinemia
Inflammation
Atherosclerosis
•
•
•
•
•
Coronary arteries
Carotid arteries
Cerebral arteries
Aorta
Peripheral arteries
CVD
Hypercoagulability
Impaired
Fibrinolysis
Endothelial
Dysfunction
Despres JP, et al. Abdominal obesity and metabolic syndrome. Nature. 2006;444:881-887.
CVD: Cardiovascular
disease
Men
300
Women
267
250
200
200
Incidence of
CVD
per 1,000
150
125
105
121
128
100
50
0
<100 110-129 130+
<110 110-129 130+
n=56 n=75 n=30 n=191 n=199 n=78
*Metropolitan Relative Weight percent
(percentage of desirable weight)
Hubert HB et al. Circulation. 1983;67:968-977

Lifestyle modification
• Reduce caloric intake by 500-1000
kcal/day (depending on starting weight)
• Target 1-2 pound/week weight loss
• Increase physical activity
• Healthy diet
• Diabetes Prevention Program
• DASH diet
Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults: The Evidence
Report. NIH Publication # 98-4083, September 1998, National Institutes of Health. Diabetes Prevention Program
(DPP) Diabetes Care 25:2165–2171, 2002. The Seventh Report of the Joint National Committee on Prevention,
Detection, Evaluation, and Treatment of High Blood Pressure, NIH Publication No. 04-5230, August 2004


Consider pharmacologic treatment
• BMI 30 with no related risk factors or diseases,
or
• BMI 27 with related risk factors or diseases
• As part of a comprehensive weight loss program
incl. diet & physical activity
Consider surgery
• BMI 40 or
• BMI 35 with comorbid conditions
Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults: The Evidence
Report. NIH Publication # 98-4083, September 1998, National Institutes of Health. Diabetes Prevention Program
(DPP) Diabetes Care 25:2165–2171, 2002
• Desirable — Less than 200 mg/dL
• Borderline high risk — 200–239 mg/dL
• High risk — 240 mg/dL and over
American Diabetes Association. Understanding Cardiometabolic Risk: Broadening Risk Assessment and
Management, Dyslipidemia Richard M Bergenstal, MD International Diabetes Center
Increased:
Decreased:
 Triglycerides
 VLDL
 LDL and small
dense LDL
 ApoB
 HDL
 Apo A-I
American Diabetes Association. Diabetes Care. 2007;30:S4-41.
• Cigarette smoking
• Hypertension (≥140/90 mm Hg or on
antihypertensive medication)
• Low HDL-C (<40 mg/dL)
• Family history of early heart disease
• Age (men ≥45 years; women ≥55 years)
 Statins (also called HMG-CoA reductase inhibitors)
work by increasing hepatic LDL-C removal from the
blood.
 Resins (also called bile acid sequestrants) bind to bile
acids in the intestines and prevent their reabsorption,
leading to increased hepatic LDL-C removal from the
blood.
 Cholesterol absorption inhibitors help lower LDL-C by
reducing the amount of cholesterol absorbed in the
intestines; increases LDL receptor activity.
 Fibrates (also called fibric acid derivatives) activate an
enzyme that speeds the breakdown of triglyceriderich
lipoproteins while also increasing HDL-C.
 Niacin (also called nicotinic acid) reduces the liver’s
ability to produce VLDL. When given at high doses, it
can also increase HDL-C.
American Diabetes Association. Understanding Cardiometabolic risk: Broadening risk Assessment and
Management, Dyslipidemia Richard M Bergenstal, MD International Diabetes Center
 For patients >20 years of age, cholesterol
should be checked every 5 years
 Ordering a fasting lipid panel is preferred to
gauge the patient’s total cholesterol, LDL-C,
HDL-C and triglycerides
 Treatment priorities
LDL-C-lowering
Category of risk
LDL-C Goal
0-1 risk factor*
< 160 mg/dL or lower
Multiple (2+) risk factors*
< 130 mg/dL or lower
People with coronary heart < 100 mg/dL or lower
disease or risk equivalent
(e.g., diabetes)
< 70 mg/dL or lower
Known CAD and DM
may be ideal





Improve glucose control if diabetes is present
Weight loss if overweight
Daily exercise
Smoking cessation
Dietary modifications including low saturated fat
(fat intake less than 30% of total calories and
saturated fat less than 7% of total calories), low
cholesterol (no more than 200 mg daily) diet
 Pharmacologic treatment frequently necessary
 Risk factors include hypertension; HDL < 40;
family history of MI before age 55; male > 45
years old; female > 55 years old; smoking.
3
2.5
Relative Risk
Women
Men
n=5,127
2
1.5
1
0.5
0
50
100
150
200
250
300
350
400
Triglyceride Level, mg/dL
Castelli WP. Epidemiology of triglycerides: a view from Framingham American Journal of Cardiology. 1992;70:3H-9H.
Mean Steady State
Plasma Glucose (mmol/L)
at Identical Plasma Insulin
12
(n=19)
10
8
(n=29)
(n=52)
6
4
2
0
A
Larger LDL particle
pattern
Intermediate
pattern
B
Small LDL particle
pattern
LDL-Size Phenotype
Reaven GM, et al. J Clin Invest. 1993;92:141-146.
Risk of CHD
3.0
2.0
1.0
25
0.0
65
100
160
220
45
85
LDL-C (mg/dL)
Gordon T, Castelli WP, Hjortland MC, Kannel WB, Dawber TR. High density lipoprotein as a protective factor against
coronary heart disease. The Framingham Study. American Journal of Medicine. 1977;62:707-14.
Persons without Diabetes

Test at least every 5 years, starting at age
20, including adults with low-risk values
Persons with Diabetes


In adults, test at least annually
Lipoproteins: measure at after initial blood
glucose control is achieved as hyperglycemia
may alter results
Preventing Cancer, Cardiovascular Disease, and Diabetes: A Common Agenda for The American Cancer Society, the American Diabetes
Association, and the American Heart Association. Circulation. 2004;109:3244-3255. American Diabetes Association. Standards of Medical
Care in Diabetes 2007. Available at: http://care.diabetesjournals.org/cgi/reprint/30/suppl_1/S4
Total
<200 mg/dL
LDL
<70 mg/dL
HDL
>40 men mg/dL
>50 women mg/dL
< 150 mg/dL
Triglycerides
Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of
High Blood Cholesterol in Adults (Adult Treatment Panel III); National Cholesterol Education Program, National Heart, Lung,
and Blood Institute, National Institutes of Health. NIH Publication No. 01-3670, May 2001
 Lifestyle modification
• Increased physical activity
• Diet: reduced saturated fat, trans fat,
•
and cholesterol
Weight loss, if indicated
American Diabetes Association. Diabetes Care. 2007;30:S4-41.

Pharmacologic treatment: primary goal is LDL
lowering
•
Without overt CVD: If over 40, statin therapy
recommended to achieve 30-40% LDL reduction
• With overt CVD: All patients should receive statin therapy
to achieve 30-40% LDL reduction
•
Lowering triglycerides and raising HDL with a fibrate is
associated with fewer cardiovascular events in patients
with clinical CVD, low HDL, and near-normal LDL
American Diabetes Association. Diabetes Care. 2007;30:S4-41.
Persons without Diabetes
 BP should be measured at
each regular visit or at
least once every 2 years if
BP <120/80 mmHg
 BP measured seated after
5 min rest in office
Persons with Diabetes
 BP should be measured
at each regular visit
 BP measured seated
after 5 min rest in office
 Patients with ≥130 or
≥80 mmHg should have
BP confirmed on a
separate day
Preventing Cancer, Cardiovascular Disease, and Diabetes A Common Agenda for the American Cancer Society, the
American Diabetes Association, and the American Heart Association. Circulation. 2004;109:3244-3255. American
Diabetes Association. Diabetes Care. 2007;30:S4-41.
Non-pharmacologic
 DASH diet
• Dietary Approaches to Stop Hypertension
• High in whole grains, fruits, vegetables,
and low-fat dairy
• Low in saturated and trans fat, cholesterol
 Physical Activity
 Weight loss, if applicable
The Dash Diet. http://dashdiet.org. American Diabetes Association. Diabetes Care. 2007;30:S4-41.
Pharmacologic
 Drug therapy indicated if BP ≥140/ ≥90 mm Hg
 Combination therapy often necessary
 Treatment should include ACE or ARB
 Thiazide diuretic may be added to reach goals
 Monitor renal function and serum potassium
The Dash Diet. http://dashdiet.org. American Diabetes Association. Diabetes Care. 2007;30:S4-41.
Microvascular
 Renal disease
 Autonomic
neuropathy
 Eye disease
(glaucoma,
retinopathy with
potential blindness)
Macrovascular
 Cardiac disease
 Cerebrovascular
disease
 Reduced survival and
recovery rates from
stroke
 Peripheral vascular
disease
American Diabetes Association. Diabetes Care. 2007;30:S4-41..
 35% of coronary heart disease deaths in
the US can be attributed to an inactive
lifestyle*
 Consistent exercise can reduce CVD risk*
 Exercise, combined with healthy diet and
weight loss, is proven to prevent/delay
onset of type 2 diabetes
* American Diabetes Association. Diabetes Care. 2007;30:S4-41.
 Diabetes Prevention Program Diabetes Care 25:2165–2171, 2002.
Guidelines
 Fit into daily routine
 Aim for at least 150 minutes/week of moderate
aerobic exercise
 Start slowly and gradually build intensity
 Wear a pedometer (10,000 steps)
 Encourage patients to take stairs, park further
away or walk to another bus stop, etc.
American Diabetes Association. Diabetes Care. 2007;30:S4-41.
Benefits of Exercise
 Increased insulin sensitivity
 Improved lipid levels
 Lower blood pressure
 Weight control
 Improved blood glucose control
 Reduced risk of CVD
 Prevent/delay onset of type 2 diabetes
American Diabetes Association. Diabetes Care. 2007;30:S4-41.
 Peripheral neuropathy can cause loss of
sensation in feet; educate about preventive
care measures for foot protection
 Pre-existing CVD can cause arrhythmias,
myocardial ischemia, or infarction during
exercise
 In presence of PDR or severe NPDR, vigorous
exercise or resistance training may be
contraindicated because of risk of vitreous
hemorrhage or retinal detachment
American Diabetes Association. Diabetes Care. 2007;30:S4-41.
Hazards Ratio (95% CI)
Never Smoked
Ex-Smoker
Current Smoker
1
1.08 (0.75 - 1.54)
1.58 (1.11 - 2.25)
R C Turner, H Millns, H A W Neil, I M Stratton, S E Manley, D R Matthews, and R R Holman. Risk factors for
coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom prospective diabetes
study (UKPDS: 23) BMJ. 1998;316:823-828.
 Obtain documentation of history of tobacco use
 Ask whether smoker is willing to quit
– If no, initiate brief, motivational discussion
regarding:
• the need to stop using tobacco
• risks of continued use
• encouragement to quit, as well as support
when ready
– If yes, assess preference for and initiate either
minimal, brief, or intensive cessation counseling.
.
American Diabetes Association. Diabetes Care. 2004;27:S27:S74-S75




Set a Plan
Offer counseling and referrals
Offer medication assistance
Offer combined pharmacologic and
behavioral intervention
.
American Diabetes Association. Diabetes Care. 2004;27:S27:S74-S75
 Proinflammatory/prothrombotic factors
underlie cardiometabolic risk
 Inflammation is a major component of
atherogenesis and other cardiometabolic
problems
 Obesity is associated with inflammation
Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med. 1999;340:115-126. Ballantyne CH, Nambi V.
Markers of inflammation and their clinical significance. Atherosclerosis suppl 2005; 6: 21-9. McLaughlin T et al.
Differentiation between obesity and insulin resistance in the association with C-reactive protein. Circulation.

High-sensitivity CRP tests may be used to further
evaluate underlying risk
Relative risk categories
• Low risk
<1 mg/L
• Average risk
1-3 mg/L
• High risk
>3 mg/L
 Aspirin and statins reduce CRP levels
 Unclear whether CRP should be a treatment target
 Reduce weight
Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med.1999;340:115- 126. Ballantyne CH.
 Pre-diabetes is an important risk factor for
future diabetes and cardiovascular disease
 Recent studies have shown that lifestyle
modification can reduce the rate of
progression from pre-diabetes to diabetes
American Diabetes Association, Diabetes Care. 2007:30:S4-41..
Fasting Plasma
Glucose
Any abnormality
must be repeated
and confirmed on
a separate day*
Diabetes Mellitus
2-hour Plasma
Glucose On OGTT
Diabetes Mellitus
126 mg/dL
200 mg/dL
Impaired Glucose
Tolerance
Impaired Fasting
Glucose
100 mg/dL
140 mg/dL
Normal
Normal
“Pre-Diabetes”
* One can also make the diagnosis of diabetes based on
unequivocal symptoms and a random glucose >200 mg/dL
Adapted from The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.
Diabetes Care 2004; Supplement 1
Results:
 Treat IFG and IGT with aggressive
lifestyle modification
 For certain patients with both IFG and
IGT consider metformin
Nathan D, et al. Impaired Fasting Glucose and Impaired Glucose Tolerance: Implications for Care.
Diabetes Care. 2007 30: 753-759.
40
Cumulative Incidence
of Diabetes (%)
Placebo
30
Metformin
20
Lifestyle
10
0
0
0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0
Years
Knowler WC, et al. NEJM. 2002;346:393-403.
Behavior
Medication
Study
Subjects
Intervention
Relative Risk
Reduction
Finnish DPS
IGT
Lifestyle
58%
IGT
Lifestyle
58%
IGT
IGT
Metformin
Acarbose
31%
25%
US DPP
US DPP
STOPNIDDM
TRIPOD
XENDOS
DREAM
Troglitazone
Prior GDM
Orlistat
IGT
Rosiglitazone/Ramipril
IGT
55%
45%
61%/NS
A1C*†
<7.0%
Preprandial
glucose
90-130 mg/dL
Postprandial
plasma glucose
<180 mg/dL
* For non-pregnant individuals
† As close to normal (<6%) as possible without
significant hypoglycemia
American Diabetes Association. Diabetes Care. 2007:30:S4-41..
 Fasting plasma glucose at least every 3 yrs

starting at age 45
Consider at younger age, or more frequently, if
patient is overweight and has one or more of the
following risk factors (or two if not overweight):
• Family history of diabetes
• Overweight (BMI 25 kg/m2)
• Habitual physical inactivity
(continued)
American Diabetes Association. Diabetes Care. 2007:30:S4-41..
Additional risk factors:
• Race/ethnicity (e.g., African-Americans, HispanicAmericans, Native Americans, Asian-Americans,
and Pacific Islanders)
• Previously identified IFG or IGT
• Hypertension (140/90 mmHg in adults)
• HDL cholesterol (35 mg/dl [0.90 mmol/l] and/or a
triglyceride level 250 mg/dl [2.82 mmol/l])
• History of GDM or delivering baby weighing >9 lbs
• Polycystic ovary syndrome (PCOS)
American Diabetes Association. Diabetes Care. 2007:30:S4-41..
 Age
47
 Race/ethnicity
African American
 Gender
Male
 Family history
HTN and diabetes
 Overweight/obesity BMI = 29
 Abnormal lipid metab TC = 210
 Hypertension
BP = 146/86
 Smoking
1 pack per day
 Physical Inactivity
Sedentary
 Unhealthy diet
Fast food diet

Identify at-risk patients by evaluating a
spectrum of predisposing risk factors

The existence of any one risk factor is an
alert to evaluate patient for others

Integrate evidence-based risk management
strategies to target modifiable risk factors
Kahn, et al. The Metabolic Syndrome: Time for a Critical Appraisal: Joint Statement From the American
Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2005;28 (9)2289-2304.